Osteoporosis, and resulting osteoporotic fractures, are major health problems in the United States. Whereas age and gonadal hormone deficiency are well known to be major risk factors for osteoporosis, other causes of osteoporosis are increasingly recognized as contributing to accelerated bone loss and increased fracture incidence. Recent studies have found a high frequency of secondary causes of osteoporosis in asymptomatic women with osteoporosis: medication use contributed to bone loss in 53%, hormonal and metabolic abnormalities in 44%, and chronic diseases of the gastrointestinal tract, chronic obstructive pulmonary disease, organ transplantation, autoimmune diseases, genetic diseases, and marrow-based and neoplastic disorders in 18% in aggregate. Consequently, recognition of novel factors leading to osteoporosis is important from both a preventative and a therapeutic perspective. In considering other potential causes of bone loss, clinical cases of unexplained osteoporosis in patients with chronic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) prompted us to examine this as another potential cause of accelerated bone loss. Using an animal model of chronic stable hyponatremia developed in this laboratory, the preliminary studies presented in this grant application verify that chronic hyponatremia is associated with severe osteoporosis in both young and aged rats, and suggest a direct effect of low sodium levels to stimulate osteoclast-mediated bone resorption. Moreover, analysis of human data from the Third National Health and Nutrition Examination Survey (NHANES III) showed a significantly increased odds ratio for osteoporosis in the hip among U.S. adults e50 years with hyponatremia compared to those with normal serum sodium levels. In view of the high reported prevalence of hyponatremia in geriatric patients (7-35%) coupled with a recently discovered association between gait instability and falls in patients with even asymptomatic hyponatremia, any additional increased risk of accelerated osteoporosis in this vulnerable aged population would be of great concern. These studies will therefore directly address the hypothesis that hyponatremia represents a previously unrecognized cause of osteoporosis, and is a contributing factor to the high morbidity and mortality from bone disease and fracture in our elderly population.Hyponatremia, or low sodium concentrations in the blood, occurs in 7-35% of geriatric patients. Recently, this disorder has been shown to cause gait instability and an increased incidence of falls in patients. Our preliminary studies have shown that hyponatremia also causes significant bone loss in animals, and is independently associated with an increased risk of osteoporosis in humans. The studies in this grant application will ascertain to what degree hyponatremia is a previously unrecognized cause of osteoporosis, which may contribute to the high morbidity and mortality from bone disease and fracture in our vulnerable elderly population.